Many diseases and/or disorders are essentially inflammatory. A main existing problem associated with the treatment of inflammatory diseases is the lack of efficacy and/or the presence of common side effects. Inflammatory diseases affecting humans include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis, dermatitis and the like. Inflammation is a common cause of pain, which can be caused by a variety of reasons, such as infection, surgery, or other injuries. Meanwhile, some diseases, including malignant tumor and cardiovascular disease, also have the symptoms of inflammation.
Prostaglandin E2 (prostaglandin E2, PGE2) is one of the most common prostaglandins (PG), which belongs to strong proinflammatory mediator and can induce fever and pain, and participate in a variety of physiological and pathological processes of the body. Its chemical synthesis consists of three consecutive enzymatic reactions: (1) arachidonic acid (AA) is released from glycerol phospholipid on the membranes by the catalysis of the phospholipase A2 (PLA2); (2) AA generates PGG2 and PGH2 by the action of cyclooxygenase (COX); and (3) PGH2 generates PGE2, PGF2, and PGD2, prostacylin and thromboxane A2 by the catalysis of PGE2 synthase (PGES).
There are two forms of cyclooxygenase (COX). One is constitutively expressed as COX-1 in many of the cells and tissues, and the other is COX-2 induced by proinflammatory stimulators such as cytokines during an inflammatory reaction. Currently, there are kinds of COX-1 and/or COX-2 inhibitors that control inflammation by reducing the final formation of PGE2, such as “NSAID” (non-steroid anti-inflammatory drug) and “coxib” (selective cox-2 inhibitor). However, inhibiting target COX will reduce the generation of all the metabolites from arachidonic acid (AA), including some metabolites that are beneficial to the human body. Therefore the COX inhibitors may cause adverse biological effects to the human body. Therefore, developing more safe and effective new drugs for inflammatory disease is of great clinical significance and market value.
The PGES targeting PGE2 synthesis is a terminal rate-limiting enzyme during the process of synthesis of PGE2. As we all know, there are at least three kinds of PGES, named cytoplasmic PGES (cPGES) (or called PGE-3), membrane-bound PGES-1 (mPGES-1) and membrane-bound PGES-2 (mPGES-2). The cPGES is a GSH dependent constitutively expressed enzyme, which belongs to the enzyme widely expressed by housekeeping genes in multiple tissues and cells and is not affected by inflammation stimulating factor. The mPGES-2 is a GSH independent constitutively expressed enzyme, which is mainly expressed in tissues with relatively low expression of mPGES-1, such as brain, heart, kidney, and intestine, and is not induced by tissue inflammation and damage. The mPGES-1 belongs to the GSH dependent inducible expression enzyme, which can be expressed a lot due to inducement by inflammatory factor and plays an important role in a variety of diseases, such as arthritis, inflammation-associated fever and pain, atherosclerosis, and the pathological and physiological process of cancer. mPGES-1 gene is on the chromosome 9q34.3, and contains three exons and two introns, with a length of approximately 14.8 Kb. Its cDNA encodes a polypeptide containing 152 amino acids. The mPGES-1 primary protein structure from different species has more than 80% homology. The research shows that the expression of COX-2 and mPGES-1 are significantly increased in a variety of cultured cells stimulated with an inflammatory factor (LPS, IL-1, etc.), which is accompanied by an increase of the synthesis of PGE2. Immunohistochemical experiments also show that COX-2 and mPGES-1 are all located in the microsome membrane, which indicates that mPGES-1 is mainly coupled with COX-2, and mediates the increased synthesis of PGE2 in the delayed reaction caused by inflammation factors. However, enzymatic dynamics research shows that the inductions of COX-2 and mPGES-1 are not completely consistent, and in certain cases, COX-2 can be coupled with mPGES-2, and mPGES-1 can also be coupled with COX-1 at the same time. Moreover, PGH2 generated by the catalysis of COX-2 either can be synthesized into PGE2 or other types of prostaglandin by the action of mPGES-1. Thus, the regulatory mechanisms of the expression of COX-2 and mPGES-1 are both overlapping and different.
Currently, there are two kinds of mPGES-1 inhibitors, AAD-2004 of Korean GNT (Neurotech) pharmaceutical company and LY-3023703 of Eli Lilly Company. AAD-2004 indications are not aimed at pain, but it is a potent spin trapping molecule and microsomal prostaglandin E synthase-1 inhibitor which can be used in the treatment of Alzheimer's disease, Parkinson's disease and motor neurone disease. LY-3023703 is used in the treatment of osteoarthritis pain, and entered the clinical stage on June 2016.
At present, there are only two patent applications WO2012087771 and WO2012161965 about mPGES-1 disclosed by Eli Lilly Company.
Although a series of microsomal prostaglandin E synthetase-1 (mPGES-1) inhibitors have been disclosed by now, new compounds with better efficacy still need to be developed. The present invention obtained a series of compounds of general formula (I) upon continuous efforts, and found that these compounds have excellent effect and function.